tbuckley/cabot-search huggingface dataset:
A survey on the detection of hepatitis B virus (HBV) in blood samples of patients with hepatocellular carcinoma (HCC) in China.
Authors: Biwei Gao, Ruilian Xu, Bo Hu
Journal: Journal of Clinical Oncology (2023)

e16178 Background: China is the country with the highest occurrence of HCC, accounting for about 45.3% of the new cases in the world. HBV can cause chronic infection and potentially leads to the occurrence of HCC. Generally, HBV genomic segments are able to be integrated into the host’s genome, then affect the expression of host genes, form carcinogenic proteins and cause chromosomal aberrations in host cells. HCC tumor tissue samples have more integration sites of HBV on the genome compared with para-cancerous tissues. It suggests that HBV is likely to be continuously enriched and integrated in the host genome during the development of HCC, and promotes the occurrence of HCC. There is plenty of tumor molecular information in the blood plasma of patients. Features of virus integration patterns and relatively quantitative level of virus DNA in the blood plasma should be intriguing to study. Methods: 216 blood samples of 178 HCC Chinese patients were collected. Circulating cell-free DNA (cfDNA) was processed by hybridization-based target enrichment and sequenced by next-generation sequencing (NGS) technique using Haplox HapOnco 680 panel. Results: In the blood of 178 HCC patients, the cfDNA of a total of 58 patients was detected with HBV genome fragments integration. These HBV genome fragments mainly belong to two subtypes, HBV-B and HBV-C, of which single HBV-B type was detected in 18 cases, accounting for 31% of HBV integrated infections, single HBV-C type was detected in 39 cases, accounting for 67.2% of HBV integrated infections. Additionally, HBV-B and HBV-C were co-integrated in 1 case. In the integrated host genome, the average number of breakpoints produced by HBV-B infection was 3.158, and the most frequent integration site was ANKRD26P1 (6 times). The average number of breakpoints produced by HBV-C integration was 3.65, and the most frequent integration site was TERT (15 times). There was no significant difference in the number of breakpoints produced between HBV-B and HBV-C groups (p=0.49). In the total of 58 HBV-B datasets and 64 HBV-C datasets, the average abundance of integrated HBV-B reads was 5.6e-05, and the average abundance of HBV-C was 5.04e-0.5, and there was no significant difference between them (p = 0.71). Conclusions: Approximately one third of the 178 HCC patients were detected positive for HBV integrationin their blood samples, with the ratio of subtypes HBV-B and HBV-C roughly 1:2. HBV-B is slightly lower than HBV-C in the number of average breakpoint, but the difference is not significant. Similarly, the overall abundance of HBV-B and HBV-C of integrated reads in blood is also quite similar. However, the hotspot integration sites of HBV-B and HBV-C on the host genome are quite different.
Efficacy of vemurafenib based regimens in colorectal cancer: A systematic review of clinical trials.
Authors: Wajeeha Aiman, Murad Qirem, Osama Alkhlaifat, Jose Garcia, Ummul Asfeen, Samer Jumean, Mohammad Nabil Rayad, Sindhusha Veeraballi, Theodore DaCosta, Gunwant K. Guron, Hamid Salim Shaaban
Journal: Journal of Clinical Oncology (2023)

e15566 Background: Colorectal cancer (CRC) is the 3 rd most common cancer worldwide, and BRAF gene mutation is present in almost 10% of these cancers. It results in constitutive activation of the mitogen-activated protein kinase pathway (MAPKP). Abnormal activation of MAPKP leads to uncontrolled mitotic activity and inhibition of apoptosis. In this systematic review, we will assess the efficacy of vemurafenib (BRAF inhibitor) based regimens in CRC. Methods: We followed PRISMA guidelines to conduct this systematic review. A literature search was performed on PubMed, Clinicaltirals.gov, and Embase with mesh terms, ‘’Colorectal Neoplasms’’ and “Proto-Oncogene Proteins B-raf” from the inception of data till 01/05/2023. We screened 4572 articles and included 1 randomized clinical trial (RCT, N = 100), and 4 non-randomized trials (nRCTs, N = 85), measuring the efficacy of vemurafenib (V) based regimens in BRAF V600E-mutated CRC. Results: In 5 clinical trials (N = 185), 90 patients were treated with triple therapy, 45 with dual therapy, and 50 were in the control arm. In triple therapy, 69 patients were treated with V plus irinotecan (I) and cetuximab (C), overall response rate (ORR) was 17% and 35%, and progression-free survival (PFS) was 4.2 and 7.7 months in the randomized and the non-randomized study, respectively. PFS was improved significantly with a hazard ratio (HR) of 0.50 (95% CI, 0.32 to 0.76, P = .001) in favor of V+I+C compared to C+I. Among combinations of V+C, adding 5-fluorouracil/leucovorin/irinotecan (FOLFIRI) as third combination showed the highest ORR of 81% and overall survival (OS) and PFS of 15.4 and 9.7 months, respectively. In two drug regimens, V was combined with Cobimetinib (Co) and Panitumumab (P) in two non-randomized studies, and partial response (PR) was 26% and 13%, respectively. (Table 1). Conclusions: BRAF + EGFR inhibitor combination is showing promising antitumor effects, and the addition of the FOLFIRI regimen was more effective than adding irinotecan alone while comparing treatment regimens in BRAF V600E-mutated CRC patients with metastasis. V+Co showed antitumor effects in CRC BRAF mutated patients who were heavily pre-treated. More randomized trials needed. [Table: see text]
Programmed cell death ligand 1 (PD-L1) expression landscape and its relationship with tumor mutational burden (TMB) in a community-based cancer center patient population in rural central Nebraska.
Authors: Mehmet Sitki Copur, Tonya Peterson, Kathryn Doornbos, Soe Min Tun, Carlene R. Springer, Leslie Robbins, Jessica Arbogast, Chandra Muske, Lisa Buescher, Jordan Sukup, Lisa Buescher, Adam Horn, Whitney Wedel, Nicholas Lintel, Kathryn Brunt, Randall Duckert, Swathi Lavudi
Journal: Journal of Clinical Oncology (2023)

e15141 Background: PD-L1 and TMB are the most widely used immunotherapy biomarkers to identify populations who would benefit from immunotherapy, with the higher values predicting better therapeutic efficacy. We sought to explore the occurrence and correlation of these two biomarkers in a community based cancer center patient population in rural central Nebraska. Methods: One hundred sixty consecutive cancer patients(pts) diagnosed and treated between 2018-2022 at Morrison Cancer Center were evaluated. Malignant tumor tissue specimens were analyzed for PD-L1expression and TMB (Foundation test). PD-L1 expression was classified as low ( &lt; 1%), intermediate (1% ≥ PD-L1 &lt; 50%), high (≥ 50%), and TMB classified as low [1–5 mutations/Megabase (muts/Mb)], intermediate (6–19 muts/Mb), high (≥ 20 muts/Mb)]. PD-L1 and TMB values were treated as continuous variables to calculate a Pearson correlation coefficient and p value. Results: Mean age at diagnosis was 64 years (range 33-89). Malignant histology diagnoses included 55 pts with lung, 18 colorectal, 12 breast, 15 unknown primary, 15 pancreas, 10 renal, 3 melanoma, 1 thyroid, 6 ovary, 5 uterus, 5 head and neck, 5 prostate, 5 biliary, and 1 vulvar. Fifty four percent (86/160) of pts had low, 33% (53/160) had intermediate, and 13% (21/160) had high PD-L1 expression score with a mean PD-L1 value of 13.8% (range 0-100). Sixty six percent (106/160) of pts had low, 30% (48/160) had intermediate, and 4% had high TMB with a mean TMB value of 5.6 muts/Mb (range 0-66). A marginal linear correlation between PD-L1 expression and TMB was observed (Pearson Correlation Coefficient = 0.172, P = 0.0270). Conclusions: PD-L1 and TMB are both important biomarkers for immunotherapy. Increasing availability and use of both PD-L1 and TMB testing in the community oncology practice beseeches the question of frequency of these two biomarkers in various cancers in the community oncology patient population as well as any association between them. The results of our study gives a glimpse of the distribution landscape of these two biomarkers for community oncology patients and suggest that PD-L1 and TMB may be independent markers with a weak association. PD-L1 and TMB may each inform use of immunotherapy by different mechanisms. [Table: see text]
Genomic profiles of chromosome remodeling pathway and their correlation with TMB, MSI, PD-L1, and immune microenvironment in biliary tract tumors.
Authors: Ningjia Shen, Xintong Shi, Yongjie Zhang, Xuefeng Zhong, Mengli Huang
Journal: Journal of Clinical Oncology (2023)

e16181 Background: Immunotherapy combined with chemotherapy has become a promising first-line treatment for biliary tract tumor (BTC) patients. A previous clinical trial with a small sample size revealed that impaired functions of chromatin remodeling genes might be a potential predictive biomarker of combined immunotherapy for BTC. However, genomic profiles of chromosome remodeling pathway and their correlation with tumor mutation burden (TMB), microsatellite instability (MSI), programmed death ligand-1 (PD-L1) and immune microenvironment in Chinese BTC patients remain unknown. Methods: A total of 2031 BTC patients (cholangiocarcinoma [CCA], N=1476; gallbladder carcinoma [GBC], N=555) were included in this study, and their tumor tissue samples were subject to next generation sequencing using a 733-gene panel. Multiple immunofluorescence using for immune microenvironment related markers (including PD-1, PD-L1, CD8, CD68, CD163, CD3, CD4, CD20, CD56 and FoxP3) detection was conducted in 49 patients. Prognostic survival data were obtained from two clinical sequencing cohorts (CCA: ICGC-2017, N=417; GBC: MSK-2022, N=233) and were used to explore the association between chromatin remodeling genes mutation and prognosis. Results: In total, 57.9% (1175/2031) of BTC patients harbored alternations in genes involved in chromatin remodeling pathway and the top three alteration frequency somatic genes were ARID1A (19%), KMT2C (11%), ARID2/KMT2D/PBRM1 (8% each), respectively. The commonly alternation types were missense (48%), frameshift indel (25%) and nonsense (17%), respectively. The TMB level of altered group was significantly higher than wild group (median TMB, mutant-type vs. wild-type = 6.145 vs. 3.352 Muts/Mb, P&lt;0.0001), but no significant difference was found in the PD-L1 expression level between the two groups. A total of 43 patients were identified as MSI-high, all of whom harbored alternations in genes involved in chromatin remodeling pathway. Compared with the wild group, the infiltration level of CD20+ B cells in tumor parenchyma was significantly higher in the altered group. Furthermore, there was no difference in overall survival (OS) between altered group and wild group (median OS, 18.99 vs. 20.97 months; HR=1.164 [95%CI: 0.9048-1.498], P=0.2360) in two clinical sequencing cohorts without immunotherapy. Conclusions: The results revealed the molecular basis of chromosome remodeling genes as the predictive biomarker of combined immunotherapy for BTC and exclude its effect on prognosis.
Phase 1b/2 dose expansion, open-label study to evaluate safety and anti-tumor activity of intravesical instillation of TARA-002 in adults with high-grade non-muscle invasive bladder cancer.
Authors: Wei Sun, Jathin Bandari, Jacqueline Zummo, Khushboo Belani, Eppie Brown, Andrea DiFiglia, McKenna Metcalf, Nuwan Nanayakkara
Journal: Journal of Clinical Oncology (2023)

TPS4618 Background: Bladder cancer is the most common malignancy involving the urinary system, with over 700,000 individuals living with bladder cancer in the US in 2019. In the US, approximately 80,000 new cases and 18,000 deaths occur each year due to bladder cancer. Approximately 70% of new urothelial bladder cancer cases are classified as non-muscle invasive bladder cancer (NMIBC). With the current Bacillus Calmette-Guerin (BCG) shortage and limited effective alternate therapies, there continues to be a significant unmet need for treatment options for patients with NMIBC. TARA-002 is being developed for intravesical instillation for the treatment of high-grade (HG) NMIBC. TARA-002 is a lyophilized biological preparation for instillation containing cells of Streptococcus pyogenes (Group A, type 3) Su strain treated with benzylpenicillin. The chemical characteristics of TARA-002 are intended to be comparable to OK-432. Therefore, nonclinical and clinical evidence with OK-432 and TARA-002 support the ADVANCED-1 study (dose escalation Phase 1a [NCT05085977] and dose expansion Phase 1b/2 [NCT05085990]). The dose for the planned Phase 1b/2 study (ADVANCED-1-Ph1b/2) will be based on the recommended Phase 2 dose (RP2D) established in the Phase 1a study. Methods: ADVANCED-1-Ph1b/2 is a Phase 1b/2, dose expansion, open-label study of intravesical instillation of TARA-002 in adults with HG carcinoma in situ (CIS) NMIBC. The purpose of this study is to evaluate the safety and anti-tumor activity of TARA-002 administered intravesically for the treatment of subjects with CIS NMIBC (± Ta/T1) with active disease. The study includes approximately 102 eligible male and female subjects ≥ 18 years of age enrolled in 2 cohorts based on their prior BCG experience. Cohort A includes subjects unable to obtain BCG or subjects who have not received BCG in the last 24 months prior to CIS diagnosis, and Cohort B includes subjects with CIS who are BCG unresponsive after completion of adequate BCG therapy (at least 5 of 6 doses of an initial induction course plus either at least 2 of 3 doses of maintenance therapy or at least 2 of 6 doses of a second induction course). Those with current or a history of penicillin allergy or current evidence of any condition, therapy, or laboratory abnormality that might confound the results are excluded. The overall study duration is 6 months/24 weeks per subject for Ph1b/2-Cohort A (includes induction, reinduction [if applicable]), and 24 months/96 weeks per subject for Ph1b/2-Cohort B (includes induction, reinduction [if applicable], maintenance until 18 months). The ADVANCED-1 study started in March 2022. Phase 1a is open for enrollment. Phase 1b/2 is expected to begin enrollment in May 2023. Clinical trial information: NCT05085977 ; NCT05085990 .
Colorectal Cancer Clinical Trial Summit: Devising solutions and interventions.
Authors: Kim Newcomer, Andrea Goodman, David Fenstermacher
Journal: Journal of Clinical Oncology (2023)

e15603 Background: Only 5% of adult cancer patients enroll in cancer clinical trials; however, approximately 70% are willing to participate. The numerous gaps between patient willingness and trial participation rates suggest that enrollment in clinical trials can be challenging. The Colorectal Cancer Alliance Clinical Trial Think Tank Summit brought together multidisciplinary voices to propose solutions and tailor interventions to increase participation in colorectal cancer (CRC) clinical trials and save lives. Methods: An expert advisory committee supported the planning of the Summit by collating existing knowledge and best practices from across the field. The Alliance collected patient perspectives through interviews and aligned around three critical themes for change in CRC clinical trials. The Summit created a forum for thoughtful and strategic discussions with expert speakers and sessions to explore thematic solutions. Results: The advisory committee’s research activities and discussion identified strategic solutions across the following themes: 1. Marketing &amp; Messaging Trust in Clinical Trials; 2. Fostering Readiness for Community-Based Cancer Research, and 3. Clinical Trial Patient Navigation. There was consensus that cancer patients and the public need to be educated on the importance of clinical trial access and dispel myths about clinical trials. Messaging must be culturally competent, creating quality standards for trial awareness and participation for utilization in a marketing campaign.&amp;nbsp; Summit participants discussed barriers to clinical trial enrollment at the institutional, structural, provider, and patient levels. Collaborations with industry sponsors and partnering with community oncology programs are necessary for designing and conducting research serving the understudied and underserved. &amp;nbsp; Participants identified that navigators are crucial for decentralized clinical trials and are a key element for improving clinical trial efficiency and the patient experience. Developing and launching a centralized clinical trial navigator pilot program is necessary to ensure that navigators are knowledgeable about recruiting CRC clinical trials nationally. Conclusions: Clinical trials are essential to advancing new treatments. To extend clinical research into the community, standardized messaging is needed that dispels myths about clinical trials and highlights positive trial outcomes. By improving our overall messaging, collaboration, education, and access to resources, we can accelerate CRC clinical trial participation to improve outcomes and research answers.
Phase I trial of enzalutamide (Enz) plus the glucocorticoid receptor antagonist relacorilant (Rela) for patients with metastatic castration resistant prostate cancer.
Authors: Kunal Desai, Anthony V. Serritella, Walter Michael Stadler, Peter H. O'Donnell, Randy F. Sweis, Russell Zelig Szmulewitz
Journal: Journal of Clinical Oncology (2023)

5062 Background: Resistance to androgen receptor (AR) targeted therapies is common in mCRPC. Glucocorticoid receptor (GR) expression increases with AR inhibition in patients (pts) and blockade of GR signaling inhibits CRPC growth in preclinical models when combined with AR blockade. We thus conducted a phase I study of the combination of rela and enz in patients with mCRPC. Methods: The study used a 6+3 design to assess safety and pharmacokinetics (PK) of the 2-drug combination. The starting dose of rela 100mg/day was chosen based on current clinical studies indicating this dose was both safe for daily dosing and pharmacologically active and the starting dose for Enz was 120mg based on anticipated drug-drug interactions. Escalating doses of rela were combined with Enz 120 using pre-specified dose escalation rules. An additional 12 patients were to be assessed at the MTD to refine safety and PK profiles. Primary endpoint was safety of the combination and to establish safe and pharmacologically active doses of both agents. Key secondary endpoints were tumor response per RECIST 1.1 criteria and progression-free survival (PFS; defined as either PSA progression, radiographic progression or death). PSA was measured after 12 weeks or at the last time at which PSA data was available, including times &lt;12 weeks. Results: 35 pts were enrolled. Pts had a median age of 74 (range 62-85) and baseline PSA of 89.5 (range 7.3-2391). 100% had prior potent AR signaling inhibitor (abi or enz) with 89% receiving prior enz, 94% prior abi, 83% prior both. 69% of pts received prior docetaxel. Median PSA change was 0.1%. Enz 120mg + Rela 100mg and Enz 120+Rela 150 were found to be safe and tolerable and achieved desirable Enz PK. DLTs were noted in 3 pts at the 200mg Rela dose, which was deemed to have exceeded the MTD, which was thus defined as 150mg Rela+120mg Enz. Most common ≥ grade 3 treatment related adverse events (TRAEs) were fatigue (11% of pts), anemia (9%), abdominal pain (6%) and pericardial effusion (6%). Median PFS was 2.5 months for 21 of 35 evaluable pts. Best response per RECIST 1.1 were Not Evaluable (40%), SD (34%) &amp; PD (26%). No CR or PR were noted. Most common reasons for discontinuation from trial included progressive disease/hospice (82%), AEs (12%), physician discretion (3%) &amp; death (3%). 2 pts remain on trial as of data cutoff (12/31/22). Conclusions: The combination of enzalutamide and relacorilant was safe &amp; largely well tolerated. The majority of pts were discontinued from trial due to progressive disease or hospice. Further analyses of secondary &amp; correlative endpoints such as translational/endocrine biomarkers, GR target gene expression and circulating tumor cells are ongoing. Clinical trial information: NCT03674814 .
Influence of levothyroxine concomitant treatment on treatment responses and outcomes in patients with metastatic colorectal adenocarcinoma.
Authors: Andrea Pretta, Pina Ziranu, Clelia Donisi, Giovanna Pinna, Francesco Loi, Giulia Deias, Enrico Palmas, Erika Cimbro, Andrea Cadoni, Sara Murgia, Stefano Mariani, Daiana Rizzo, Veronica Dell'Utri, Alessandra Pia D'Agata, Fabio Bardanzellu, Antonio Maccioni, Eleonora Lai, Marco Puzzoni, Valeria Pusceddu, Mario Scartozzi
Journal: Journal of Clinical Oncology (2023)

e15593 Background: Hypothyroidism is the most common thyroid disorder and levothyroxine is the mainstay treatment. Levothyroxine is mainly used to restore the euthyroid clinical and biochemical status in the gland. Recent literature has correlated chronic hormonal treatment with adverse effects on bone and heart function, as well as correlated with an increased risk of tumor onset. Data available in the literature are controversial, therefore the aim of our study was to evaluate the correlation between chronic levothyroxine intake and outcomes and response to first line treatments in patients affected by metastatic colorectal cancer. Methods: We retrospectively collected the data from 139 patients with metastatic colorectal adenocarcinoma, belonging to the Medical Oncology Department of the University Hospital of Cagliari from 2016 to 2019. All patients enrolled in the study had received metastatic first-line treatment with doublet or triplet chemotherapy associated with anti-VEGF or anti-EGR monoclonal antibody. Patients with ECOG PS ≤1 with no more than two relevant comorbidities were included in the study. The primary objective of the study was median overall survival (mOS) and secondary objectives were: median progression free progression (PFS), median overall survival (mOS) differences between RAS wild type and mutant tumour. BRAF mutant tumors were excluded from the evaluation. Results: Median age was 65 years (±10), 51% were male and 49% were female. 63% patients had an ECOG-PS 0, while 37% had an ECOG-PS 1. 67% developed from the left colon; 33% from the right colon and the transverse colon. All patients had synchronous metastases. 18% patients took levothyroxine and 82% patients did not take it. Among the patients receiving levothyroxine therapy, 64% had a RAS wild type and 36% a RAS mutated. Levothyroxine treated patients showed a significantly lower median OS than not treated patients (15 months versus not reached, p = 0,0001). Levothyroxine treated patients also showed a significantly lower median PFS than non treated patients (6 versus 8 months, p = 0,035). Within levothyroxine treated pts, no statistically significant differences were found in mOS and mPFS between RAS wt and RAS mut (mOS 15 versus 14 months, respectively, p = 0.9; mPFS 8 versus 7 months, respectively, p = 0,7). Conclusions: The results show a possible correlation between levothyroxine therapy and outcomes in mCRC. This would deserve further study to understand further biological-molecular aspects, to date partially explained by preclinical studies, in order to clarify some of the possible underlying mechanisms.